High-Density Lipoproteins—Atherosclerosis

Nikkila, Kaste, Ehnhold and Viikari, Acta Medica Scandinavica (1978), 2002 measured serum high-density lipoprotein-cholesterol (HDL-C) levels in twenty-eight epileptic patients who received PHT. These were compared with ninety healthy controls, forty-four men and forty-nine women. The patients treated with PHT had significantly higher HDL-C levels than the controls. The authors say that serum HDL-C shows an inverse correlation with the risk of coronary heart disease, and note that some clinicians taking care of epileptic patients have been impressed by the low incidence of myocardial infarction.

2002. Nikkila, E. A., Kaste, M., Ehnholm, C. and Viikari, Elevation of high-density lipoprotein in epileptic patients treated with phenytoin, Acta Med. Scand, 204: 517-20, 1978.

Henry, Bell and Glithero, New England Journal of Medicine (1979),1893 report that nineteen patients on long term PHT therapy had significantly higher HDL-C levels (p<0.01) as compared to twenty-seven controls.

1893. Henry, D. A., Bell, G. D. and Glithero, P., Plasma high-density lipoproteins, New Eng. J. Med., 300(14): 798, 1979.

Luoma, Myllyla, Sotaniemi, Lehtinen and Hokkanen, European Neurology (1980),2734 compared HDL-C levels in ninety-seven epileptics with forty-three controls. Thirty-eight patients on PHF alone, and thirty-nine on PHT in combination with carbamazepine or phenobarbital, had in creased levels compared to controls. Patients on PHT alone had significantly higher levels than controls.

2734. Luoma, P. V., Myllyla, V. V., Sotaniemi, E. A., Lehtinen, 1. A., Hokkanen, E. J., Plasma high-density lipoprotein cholesterol in epileptics treated with various anticonvulsants, Eur. Neural., 19; 67-72,1980.

Murphy, Reddy and Marquardt, Annals of Neurology (1981),2813 in a study of HDL-C levels in children on various anti-convulsants, report that in eleven children on PHT the HDL-C levels were significantly elevated (p<0.001) compared to controls. The authors suggest that PHT may protect against atherosclerosis.

2813. Murphy, J. V., Reddy, M. N., Marquardt, K., High-density lipoprotein cholesterol concentrations in the plasma of children receiving anticonvulsants, Ann. Neurol., 10(3): 292, 1981.

Kaste, Muuronen, Nikkila, and Neuvonen, Stroke (1982),2649 and (1983),2650 measured serum HDL-C and other lipoproteins before and during PHT therapy (200-300 mg/day) in twenty-seven patients with a history of transient ischemic attacks. Nine of these patients had arterial hypertension; seven, heart disease; and four, diabetes. Three had suffered myocardial infarction and two, brain infarction. Before PHT, HDL-C levels were lower in these patients than in normal healthy controls. After one month’s treatment with PHT, HDL-C concentrations reached normal levels. After nine months of therapy, there was a mean increase in HDL-C of 42% in the males and 68% in females. Low-density lipoproteins (LDL) did not increase, so that HDL/LDL cholesterol ratios improved. Only seven patients had recurrent transient ischemic attacks. None had brain or myocardial infarction over the two-year period of PHT treatment. The authors conclude that low serum HDL-C can be increased with PHT and this could retard the development of atherosclerotic disorders such as myocardial infarction or stroke.

2649. Kaste, M., Muuronen, A., Nikkila, E. A., Neuvonen, P. J., Increase of low serum concentrations of high-density lipoprotein (HDL) cholesterol in TIA patients treated with phenytoin, Stroke, 13: 123,1982.
2650. Kaste, M., Muuronen, A., Nikkila, E. A., Neuvonen, P. J., Increase of low serum concentrations of high-density lipoproteins (HDL) cholesterol in tia-patients treated with phenytoin, Stroke, 14(4); 525-30, 1983.

O’Neill, Callaghan, Stapleton and Molloy, Acta Neurologica Scandinavica (1982),2235 measured serum total cholesterol and HDL-C in fifty-two epileptic patients taking either PHT or carbamazepine. Total cholesterol concentrations did not differ significantly from controls, but the percentage of HDL-C and its ratio to total cholesterol increased in both groups. The increase was significant for PHT. The authors point out that the change in this ratio is of particular significance because HDL facilitates the uptake of cholesterol from peripheral tissues and transports it to the liver for breakdown and excretion.

2235. O’Neill, B., Callaghan, N., Stapleton, M. and Molloy, W., Serum elevation of high density lipoprotein (HDL) cholesterol in epileptic patients taking carbamazepine or phenytoin, Acta Neural. Scand., 65: 104-9, 1982.

Danilenko and Ivaniv, Vrachebnoe Delo (1983),2428 reported the effects of PHT (300-450 mg/day for twenty days) on lipid metabolism and microsomal enzyme activity in twelve patients with atherosclerosis, mostly of the pelvis and lower extremities. PHT caused an increase in HDL-C concentrations (average 18% in arterial blood and 15% in venous blood). The ratio of HDL-C to total cholesterol also increased. The arteriovenous differences in concentration for total cholesterol, LDL and very low density lipoproteins decreased significantly. Based on their data, the authors suggest that the PHT-induced rise in HDL-C results in a decrease in cholesterol and atherogenic lipoproteins in the peripheral vessels and that this may slow the development of the atherosclerotic process.

2428. Danilenko, M. V., Ivaniv, Y. A., Corrections of hypoalphacholesterolemia in patients with atherosclerosis by means of diphenine, Vrach. Delo, 7: 72-75, 1983.

Bell and Dittmeier, Arteriosclerosis (1985), 2319 in a controlled study, investigated the effects of PHT (200 mg/day for three months) on HDL-C sub fractions (HDL2 and HDL3) in forty five patients, forty-one with angiographic confirmation of coronary artery disease. All had HDL-C to total cholesterol ratios of less than 20%. During PHT treatment, the HDL2 subfraction increased significantly in twenty-five patients. Total HDL-C also increased in twenty-nine of the forty-five patients, while mean subtraction HDL3 increased only slightly. The authors note, that since HDL2 is associated with reduced coronary heart disease, PHT may be beneficial in preventing the progression of coronary artery disease.

2319. Bell, H. H., Dittmeier, G. E., Increase in HDL2 cholesterol with phenytoin therapy, Arteriosclerosis, 5(5): 514A, 1985.

Muuronen, Kaste, Nikkila and Tolppanen, British Medical Journal (1985),2814 evaluated all deaths (1399) among epileptic patients in Finland from 1978 to 1980, and compared them with those in a control group, also 1399, matched for age, sex and date of death. Autopsies had been performed on 695 in the epileptic group and 734 in the control group. There was a 29% (p <0.001) lower mortality rate due to deaths from ischemic heart disease (258) among epileptics who had been treated with PHT, phenobarbital and/or carbamazepine compared with controls (382). Total cardiovascular mortality was also lower in the treated epileptics. In a discussion of the reasons for the lower cardiovascular mortality seen in the epileptic patients, the authors point out that PHT, carbamazepine, and barbiturates all raise plasma concentrations of high-density lipoproteins and induce microsomal liver enzymes. They note that PHT’s ability to reduce hyperinsulinemia, an independent positive risk factor in ischemic heart disease, and its antiarrhythmic actions may contribute to its protective effects. See also Refs. 1961, 2162, 2318, 2323, 2542, 2652, 2741, 2827, 2897, 2946.

2814. Muuronen, A., Kaste, M., Nikkila, E. A., Tolppanen, E. M., Mortality from ischaemic heart disease among patients using anticonvulsive drugs: a case-control study, Br. Med. J., 291: 1481-3, 1985.

1961. Linden, V., Brevik, J. I., and Hansen, T., Phenytoin, phenobarbitone and serum cholesterol, Scand. J. Soc. Med., 5: 123-5, 1977.
2162. Check, W.A., ‘A remarkable medicine’ raises HDL levels, JAMA, 247(12): 1686-7, 1982.
2318. Bell, H. H., Dittmeier, G. E., Comparative effects of gemfibrozil, phenytoin, and nicotinic acid on serum HDL, Arteriosclerosis, 5(5): 514A, 1985.
2323. Berlit, P., Krause, K. H., Heuck, C. C., Schellenberg, B., Serum lipids and anticonvulsants, Acta Neural. Scand., 66: 328-34, 1982.
2542. Glueek, C. J., Nonpharmacologic and pharmacologic alteration of high-density lipoprotein cholesterol: therapeutic approaches to prevention of atherosclerosis, Am. Heart J., 110: 1107, 1985.
2652. Kaukola, S., Manninen, V., Neuvonen, P. J., Malkonen, M., Ehnoholm, C., Effect of phenytoin on serum lipoproteins in middle-aged men, J. Cardiovase. Pharmacol., 3: 20714,1981.
2741. Luoma, P. V., Sotanierni, E. A., Pelkonen, R. O., Savolainen, M. J., Arranto, A., Enholm, C., Enzyme-inducers reduce the risk of atherosclerotic vascular disease?, Br. J. Clin. Pharmacol., 14(4): 606P, 1982.
2827. Nikkila, E. A., Kaste, M., Ehnhoirn, C., Viikari, J., Increase of serum high-density lipoprotein in phenytoin users, Br. Med. J., 99, 1978.
2897. Reddy, M. N., Effect of anticonvulsant drugs on plasma total cholesterol, high-density lipoprotein cholesterol, and apolipoproteins A and B in children with epilepsy, Proc. Soc. Exp. Biol. Med., 180(2): 354-63, 1985.
2946. Serra, S., Callito, G., DeDomenico, P., Morgante, L., Bianebi, L., Ajello, L., Musolino, R., Arena, A., DiPerri, B., Influence of antiepileptic drugs on plasma lipid levels, Acta Neural., 38(3): 190-7, 1983.

Goerdt, Keith and Rubins, Journal of Clinical Pharmacology (1995), noting that a low level of high-density lipoprotein cholesterol (HDL-C) is an important risk factor for coronary artery disease, undertook a study of the ability of PHT to increase HDL-C levels in men with low levels of HDL-C. Ninety-two elderly male outpatients with baseline HDL-C levels less than or equal to 1.16 mmol/L (45 mg/dL) participated in a randomized, placebo-controlled, double-blind clinical trial.
Participants received a placebo or PHT (100, 200 or 300 mg/day) for fourteen weeks. Lipid levels were measured at baseline and at six, ten and fourteen weeks. After fourteen weeks of treatment, the 200-mg and 300-mg phenytoin groups together achieved a significant 10% increase in HDL-C levels, compared with that of placebo (after adjusting for differences in baseline HDL-C levels, age, and body mass index). Other lipid levels did not change and were similar in the PHT and placebo groups. Average compliance was 98% or greater for each of the treatment groups. Side effects in all groups were mild and mostly transient.
The authors conclude that phenytoin is generally well tolerated, even in an elderly population with multiple chronic illnesses, and can effectively increase HDL-C levels in men with low levels of HDL-C.

Bell, Dittmeier and Martinez, Arteriosclerosis (1986), 3179 determined the effect of phenytoin on serum cholesterol (C), high-density lipoproteins (HDL), low-density lipoproteins (LDL), and triglycerides (TG) in sixty-five cardiac patients. Fifty-eight had angiographic confirmation of coronary artery disease. All patients (average age 56 years) had HDL/C ratios of less than 20%. Patients maintained a prudent diet during both the control or baseline period (three months) and the subsequent PHT-treatment period (200 mg PHT/day for three months). After PHT treatment, fifty-four of sixty-five patients (83%) had an increase in HDL or HDL. The authors conclude that PHT may be beneficial in preventing the progression of coronary artery atherosclerosis and stenosis.

3179. Bell, H.H., Dittmeier, G., Martinez, L.M., Alteration of serum lipoproteins by phenytoin, Arteriosclerosis, 6: 545-6A, 1986.

McKenney, Petrizzi, Wright, Cooper and Lambert, Arteriosclerosis (1988), 3180 studied the effect of two phenytoin doses (30 mg/day and 100 mg/day) on HDL cholesterol in a randomized, double-blind, placebo-controlled, trial involving twenty-one healthy, non-medicated male volunteers. Duplicate lipoprotein and HDL subfraction measurements were made at the end of a two-week, single-blind lead-in period and after a one-month, double-blind study period. There was no difference in HDL levels after placebo or 30 mg PHT doses. With PHT 100 mg/day, HDL cholesterol levels were increased from 51.9 to 58.9 mg/dl (13%).

3180. McKenney, J.M., Petrizzi, K.S., Wright, J.T., Cooper, L.W., Lambert, C.M., The effect of low phenytoin doses on HDL cholesterol, Arteriosclerosis, 8: 586A, 1988.

Calandre, Sinues Porta and Garcia de la Calzada, Epilepsia (1992), 3181 assessed the effect of chronic phenytoin administered as monotherapy to 100 adult epileptic patients, on total cholesterol, high-density lipoproteins (HDL), low-density lipoprotein (LDL), and very-low-density lipoprotein cholesterol, apolipoproteins A, A1, and B and gamma-glutamyltransferase (ggt) serum concentrations. In relation to 100 controls, the treated patients showed higher HDL cholesterol, apolipoproteins A and A1, and ggt levels and lower LDL cholesterol and apolipoprotein B values. The significance of the results was greater in women than in men. Among patients, ggt levels were positively correlated with PHT plasma concentrations. A negative correlation was found between the apolipoprotein A/A1 ratio and the PHT and ggt plasma levels. There was a positive correlation between the apolipoprotein A/A1 ratio and the LDL/HDL cholesterol ratio. The authors conclude that these data indicate that PHT exerts a beneficial effect on the serum lipids profile.

3181. Calandre, E.P., Sinues Porta, B., and Garcia de la Calzada, D., The effect of chronic phenytoin treatment on serum lipid profile in adult epileptic patients, Epilepsia, 33(1): 154-157, 1992.

McKenney, Petrizzi, Briggs and Wright, Pharmacotherapy (1992), 3182 reported that low doses of phenytoin (PHT) had no substantial effect on HDL cholesterol or HDL subfractions of healthy adult men (ages 18 - 45). After four weeks of treatment, mean differences between baseline and post-treatment HDL cholesterol levels with placebo (7 patients), 30 mg PHT (12 patients) and 100 mg PHT (12 patients) were 0.010 mmol/L, 0.005 mmol/L and 0.096 mmol/L respectively (p = 0.2947). Baseline and post-treatment HDL2 and HDL3 levels were not different among the groups. Total cholesterol levels were significantly higher in subjects taking 100 mg PHT than in the other two groups.

3182. McKenney, J.M., Petrizzi, K.S., Briggs, G.C., and Wright, J.T., The effect of low-dose phenytoin on high-density lipoprotein cholesterol, Pharmacotherapy, 12(3):183-188, 1992.

Zhang, Liang and Cai, National Workshop of Clinical Use of Phenytoin, Chengdu, China (1992), 3183 reported on eleven hyperlipemia patients, nine males and two females mean age of 53.00 ± 10.63 years treated with PHT. PHT dosage ranged from 200 mg ń 300 mg for a period of four to twelve weeks. Results of the study suggested that PHT is a useful treatment for hyperlipemia, especially for decreasing triglycerides.

3183. Zhang, H., Liang, D., and Cai, Y., Clinical study on the efficacy of phenytoin in hyperlipemia, Presented at the National Workshop of Clinical Use of Phenytoin, Chengdu, China, 1992.

Franceschini, Werba, D'Acquarica, Gianfranceschi, Michelagnoli and Sirtori, Clinical Pharmacology and Therapeutics (1995), 3184 compared the ability of phenytoin, a microsomal enzyme inducer, to raise plasma high-density lipoprotein (HDL) levels in normolipidemic subjects and patients with primary hypoalphalipoproteinemia. In healthy control subjects, phenytoin caused a dose-dependent increase of plasma HDL, HDL2, and HDL3 cholesterol levels, up to 40% to 50%. Minor changes were recorded in the plasma concentrations of apolipoprotein (apo) A-I and apo A-II; the plasma level of the cholesteryl ester transfer protein (CETP) decreased by 42%. In contrast, none of the patients with hypoalphalipoproteinemia had changes in plasma HDL, HDL2, or HDL3 cholesterol, apo A-I, apo A-II, or CETP levels.

3184. Franceschini, G., Werba, J.P., D'acquarica, A.L., Gianfranceschi, G., Michelagnoli, S., and Sirtori, C.R., Microsomal enzyme inducers raise plasma high-density lipoprotein cholesterol levels in healthy control subjects but not in patients with primary hypoalphalipoproteinemia, Clin. Pharmacol. Ther., 57(4):434-40, 1995.

Goerdt, Keith and Rubins, Journal of Clinical Pharmacology (1995), 3185 noting that a low level of high-density lipoprotein cholesterol (HDL-C) is an important risk factor for coronary artery disease, undertook a study of the ability of PHT to increase HDL-C levels in men with low levels of HDL-C. Ninety-two elderly male outpatients with baseline HDL-C levels less than or equal to 1.16 mmol/L (45 mg/dL) participated in a randomized, placebo-controlled, double-blind clinical trial. Participants received a placebo or PHT (100, 200 or 300 mg/day) for fourteen weeks. Lipid levels were measured at baseline and at six, ten and fourteen weeks. After fourteen weeks of treatment, the 200-mg and 300-mg phenytoin groups together achieved a significant 10% increase in HDL-C levels, compared with that of placebo (after adjusting for differences in baseline HDL-C levels, age, and body mass index). Other lipid levels did not change and were similar in the PHT and placebo groups. Average compliance was 98% or greater for each of the treatment groups. Side effects in all groups were mild and mostly transient. The authors conclude that phenytoin is generally well tolerated, even in an elderly population with multiple chronic illnesses, and can effectively increase HDL-C levels in men with low levels of HDL-C.

3185. Goerdt, C., Keith, M., Rubins, H.B., Effects of phenytoin on plasma high-density lipoprotein cholesterol levels in men with low levels of high-density lipoprotein cholesterol, J. Clin. Pharmacol., 35: 767-75, 1995.

Goerdt, Bloomfield, Rubins, Swaim and Folsom, Thrombosis Research (1995), 3186 as part of a randomized placebo-controlled study to determine whether phenytoin (100 mg, 200 mg or 300 mg daily) raises high-density lipoprotein cholesterol (HDL-C) levels in 41-81 year-old men, measured fibrinogen levels. Fifty-six patients (11 in the placebo group; and 15 in each of the three phenytoin dosage groups) had post-treatment fibrinogen levels and 20 of these patients (4, placebo; and 5, 6 and 5 in the phenytoin groups respectively) had both pre- and post-treatment (14-week) fibrinogen levels). The patients with both pre- and post-treatment measurements of fibrinogen had a 0.16 g/L decrease compared to a rise of 0.08 g/L in the placebo group, but the difference did not reach statistical significance. There did not appear to be any correlation between phenytoin levels and/or dose and change in fibrinogen level.

Despite the limitations of their small study, the authors conclude that phenytoin can produce meaningful reductions in fibrinogen levels. Since such reductions have been associated with lower 5-year coronary heart disease death rates, and since phenytoin also has the ability to raise HDL-C levels, they suggest that phenytoin could be a promising agent for the prevention of heart disease.

3186. Goerdt, C., Bloomfield Rubins, H., Swaim, W., and Folsom, A., Can phenytoin lower plasma fibrinogen concentrations?, Thrombosis Res., 79(3):231-36, 1995.

Liang, Xu, Zhang, Zhang and Miao, National Workshop of Clinical Use of Phenytoin, Chengdu, China (1995), 3187 conducted a self-controlled study to evaluate the efficacy and safety of phenytoin in the treatment of hyperlipemia in 34 gout patients. These patients were given one dose of 200 - 300 mg/day for 1 - 3 months. For 23 of the 31 patients with abnormal triglyceride (TG) levels, the therapeutic effect of PHT was positive. The mean level of TG decreased from 3.50 ± 1.84 mmol/L to 2.24 ± 0.76 mmol/L (p < 0.001) and the reduced percentage was 36.0%. For 8 of 9 patients with abnormal total cholesterol (TC), there was a reduction after PHT treatment. The mean TC level decreased from 7.20 ± 1.14 mmol/L to 6.09 ± 1.04 mmol/L (p < 0.05). TC declined by 15.42 %. A group of 15 patients with lower than 1.0 mmol/L high-density lipoprotein cholesterol (HDL-C) were also given PHT. There was a mean increase from 0.81 ± 0.11 mmol/L (p > 0.05). While there was no therapeutic effect for 6 of the patients, HDL-C levels of 9 patients increased from 0.78 ± 0.08 mmol/L to 0.91± 0.13 mmol/L (p < 0.05). After phenytoin treatment of 8 patients with abnormal levels of low-density lipoprotein cholesterol (LDL-C), there was a decline of 24 - 28 % (from 5.56 ± 1.25 mmol/L to 4.21 ± .98 mmol/L, p<0.05). For 3 patients, the abnormal VLDL-C was reduced from 1.66 ± 0.19 mmol/L to 1.49 ± 1.02 mmol/L. While the authors reported and adverse drug reaction of 5.88 %, they stated that using oral phenytoin 200 - 300 mg/day was safe. They concluded that their study suggests that phenytoin is useful in decreasing TG, TC, LDL-C and increasing HDL-C.

3187. Liang, D., Xu, N., Zhang, H., Zhang, H., and Miao, J., A self-controlled study of phenytoin in the treatment of hyperlipemia, Presented at the National Workshop of Clinical Use of Phenytoin, Chengdu, China, 1995.

Miller, Burgan, Osterlund, Segrest and Garber, Arteriosclerosis, Thrombosis, and Vascular Biology (1995), 3188 conducted a study to determine whether phenytoin raises HDL-C in nonepileptic subjects at risk for coronary artery disease. They performed a double-blind, placebo-controlled, parallel-group study in 41 subjects with reduced levels of HDL-C. Subjects were placed on an American Heart Association Step I diet and were randomized to receive either phenytoin or placebo for 3 months. Serum levels of phenytoin were monitored and adjusted to between 7.5 and 15 µg/mL. Fasting levels of lipids and lipoproteins were determined twice at baseline (weeks - 2 and - 1) and during the treatment phase of the study (weeks 11 and 12). Compared with dietery baseline, phenytoin-treated subjects experienced significant paired percent increases in total HDL-C (12.4%; p < .01), an effect confined to the HDL2 subfraction (137%; p < .01). The paired percent increases in HDL-C and HDL2 levels remained significant after adjustment for placebo (p < .05, p < .025, respectively). There were no significant differences in the paired percent changes from dietery baseline in total cholesterol, triglyceride, or LDL cholesterol levels between placebo and phenytoin-treated groups. The significant paired percent increases in total HDL-C and HDL2 from dietery baseline suggest a potential role for phenytoin in subjects with reduced levels of HDL-C. Phenytoin was well tolerated and no significant side effects were reported.

3188. Miller, M., Burgan, R.G., Osterlund, L., Segrest, J.P., and Garber, D.W., A prospective randomized trial of phenytoin in nonepiletic subjects with reduced HDL cholesterol, Arteriorscl. Thromb. Vascul. Biol., 15(12):2151-56, 1995.

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